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Post by Former NIMH Director Thomas Insel: From Cognition to Genomics: Progress in Schizophrenia Research

By Thomas Insel on November 10, 2010

This week’s issue of Nature has a special section dedicated to research progress on schizophrenia.i There have been few such issues dedicated to any medical disorder, so this is a landmark for schizophrenia research, a follow-up perhaps to an editorial in Nature at the beginning of this year predicting a “decade for psychiatric disorders”.ii But beyond the mere fact that schizophrenia has been singled out for this distinction, the contents document remarkable progress on a disorder that has been such a conundrum for the past century.

For one thing, schizophrenia can now be described as a brain disorder or, more precisely, as a disorder of brain circuits. With neuroimaging, several of the major nodes in the circuit have been identified, especially within the prefrontal cortex. A major advance has been linking changes in circuit function to cognition and behavior. As a result, we are increasingly focusing on the cognitive deficits of schizophrenia as the core problem, preceding and perhaps leading to the more obvious positive symptoms of hallucinations and delusions.

Another area of unambiguous progress has been genomics. Five years ago the field was frustrated by the lack of replicated findings. With the creation of international consortia sharing data from thousands of patients, we can now see several of the major risk genes. They are not the usual suspects, such as genes involved in dopamine or serotonin neurotransmission. Common variants in genes from the MHC complex, which is important for immune self-recognition, a gene for a transcription factor called TCF4, and several genes that encode synaptic proteins have all been found to confer increased risk. The list is probably not complete as together these explain only a fraction of the genetic risk for the disorder. Many rare variants have also been described in the past year, adding to the known major structural lesions like DISC1 and the 22q11 deletion. These rare events may explain only a small fraction of cases, but as with hypertension and cancer, even rare mutations that cause disease can yield important clues to the pathophysiology underlying more common forms of disease.

From genomics have come clues to the importance of reconceptualizing schizophrenia as a neurodevelopmental disorder. Many of the genetic factors are involved with neurodevelopment; hardly surprising as thousands of genes must be expressed in a carefully choreographed sequence to develop a healthy brain. What is unexpected is that many of the genetic variations associated with schizophrenia appear to disrupt fragments of proteins expressed only in fetal development. And experimental reductions of DISC1 transiently during fetal development in mice have profound effects on physiology and behavior, emerging only in early adulthood. These kinds of observations, along with reports of prenatal and perinatal environmental factors that increase risk for schizophrenia, point to a model of schizophrenia that begins early in life, with subtle cognitive effects through much of development, and emergence of psychosis as a late stage in early adulthood.

If psychosis is a late stage of schizophrenia, analogous to myocardial infarction in coronary artery disease, then we need to develop biomarkers for early detection and treatments that can preempt psychosis. This is where the next decade of research could lead. If the core deficits are cognitive, the “biomarker” for detection might be a working memory task or some assessment of executive function. And the treatments to preempt psychosis might not resemble anti-psychotic medications. Instead of medication, imagine brain training to rewire the circuitry just as we use exercise to reduce cardiac risk. Continuing the coronary artery disease analogy, drugs such as marijuana might be, for someone at risk for psychosis, analogous to the high lipid diet for someone at risk for coronary disease: something that needs to be avoided.

Over the past half-century, we have learned to diagnose coronary artery disease well before a heart attack using tests of cardiovascular risk factors and function. We have averted millions of cardiac deaths through preventive measures such as diet, exercise, and medications for those at risk. For the past century, schizophrenia has been defined by psychosis and we have made too little progress for too many people challenged by this disorder. This issue of Nature marks new hope that we can develop a preemptive approach to schizophrenia, as done for cardiac disease.

There have been many apparent breakthroughs for schizophrenia over the past several decades, followed by non-replication or findings suggesting lack of treatment effectiveness. Finally, we are making real progress on many fronts, from cognition to genomics. As the articles in Nature note, we still have a long way to go. But this is an important moment to recognize – the “decade for psychiatric disorders” has begun.